In this study, a system for oral delivery of oxaliplatin (OXA) was prepared for metronomic chemotherapy to enhance antitumor efficacy and modulate tumor immunity. OXA was complexed with Nα-deoxycholyl-l-lysyl-methylester (DCK) (OXA/DCK) and formulated as a nanoemulsion (OXA/DCK-NE). OXA/DCK-NE showed 3.35-fold increased permeability across a Caco-2 cell monolayer, resulting in 1.73-fold higher oral bioavailability than free OXA. In addition, treatment of the B16F10.OVA cell line with OXA/DCK-NE resulted in successful upregulation of immunogenic cell death (ICD) markers both in vitro and in vivo. In a B16F10.OVA tumor-bearing mouse model, treatment with OXA/DCK-NE substantially impeded tumor growth by 63.9 ± 13.3% compared to the control group, which was also greater than the intravenous (IV) OXA group. Moreover, treatment with a combination of oral OXA/DCK-NE and anti-programmed cell death protein-1 (αPD-1) antibody resulted in 78.3 ± 9.67% greater inhibition compared to controls. More important, OXA/DCK-NE alone had immunomodulatory effects, such as enhancement of tumor antigen uptake, activation of dendritic cells in tumor-draining lymph nodes, and augmentation of both the population and function of immune effector cells in tumor tissue as well as in the spleen; no such effects were seen in the OXA IV group. These observations provide a rationale for combining oral metronomic OXA with immunotherapy to elicit synergistic antitumor effects.

中文翻译：

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通过在多种口服纳米乳剂中掺入奥沙利铂的定量给药来调节肿瘤免疫力。

在这项研究中，制备了口服奥沙利铂（OXA）系统用于节律化疗，以增强抗肿瘤功效并调节肿瘤免疫力。OXA与Nα-脱氧胆酰基-1-赖氨酰基甲基酯（DCK）（OXA / DCK）络合，并配制成纳米乳液（OXA / DCK-NE）。OXA / DCK-NE在整个Caco-2细胞单层上的通透性提高了3.35倍，从而导致口服生物利用度比游离OXA高1.73倍。另外，用OXA / DCK-NE处理B16F10.OVA细胞系可在体内外成功地上调免疫原性细胞死亡（ICD）标记。在B16F10.OVA荷瘤小鼠模型中，与对照组相比，用OXA / DCK-NE治疗实质上抑制了63.9±13.3％的肿瘤生长，这也大于静脉（IV）OXA组。此外，与对照组相比，口服OXA / DCK-NE和抗程序性细胞死亡蛋白1（αPD-1）抗体联合治疗可产生78.3±9.67％的抑制作用。更重要的是，单独的OXA / DCK-NE具有免疫调节作用，例如增强肿瘤抗原摄取，激活引流淋巴结的树突状细胞以及增强肿瘤组织中免疫效应细胞的数量和功能，以及在脾脏中 在OXA IV组中未观察到此类影响。这些观察结果为将口服节拍型OXA与免疫疗法结合以引发协同抗肿瘤作用提供了理论依据。例如增加肿瘤抗原的摄取，引流肿瘤的淋巴结中树突状细胞的活化，以及肿瘤组织和脾脏中免疫效应细胞的数量和功能的增强；在OXA IV组中未观察到此类影响。这些观察结果为将口服节拍型OXA与免疫疗法结合以引发协同抗肿瘤作用提供了理论依据。例如增加肿瘤抗原的摄取，引流肿瘤的淋巴结中树突状细胞的活化，以及肿瘤组织和脾脏中免疫效应细胞的数量和功能的增强；在OXA IV组中未观察到此类影响。这些观察结果为将口服节拍型OXA与免疫疗法结合以引发协同抗肿瘤作用提供了理论依据。